Immunosuppression in the Prevention of Progesterone Resistance and Adverse Reproductive Outcomes in Diabetes
Diabetes is a global epidemic health adversity that is often associated with female subfertility, repeated miscarriages and congenital malformations. Despite plethora of information suggesting an association between aberrant maternal immune responses during pregnancy and gestational complications in type 1 diabetes, mechanisms underlying pre-clinical gestational loss in obese and type 2 diabetic subjects are yet to be defined. Further, no comprehensive evaluation of the impact of diabetes on implantation has been completed. This study aimed at examining effects of diabetes on the natural events associated with mammalian implantation in-vivo. Using various functional, histological and postmortem analyses, impact of diabetes and that of the macrolide immunosuppressant tacrolimus on murine implantation and post- implantation pregnancy events and outcomes were compared across mouse models of type 1 and obesity-associated type 2 diabetes, the None-Obese Diabetic and the New- Zealand Obese mice, respectively. Results obtained in this study showed, for the first time, that naturally occurring diabetes significantly impeded endometrial progesterone receptor (PGR)-mediated influences, creating a hostile uterine milieu that is not receptive to the implanting embryo. Specifically, we have identified aberrancies in the endometrial expression and regulation of certain receptivity biomarkers including those of the anti-implantation mucin MUC1 and its upstream regulators of cytokines and transcriptional factors suggestive of heightened endometrial resistivity to the hormonal actions of progesterone at implantation in diabetes. Further immunological and molecular analyses of endometria obtained from diabetic mice revealed an augmented pro-inflammatory milieu and an aberrant expression of the PGR and two of its co-regulators, namely the protein inhibitor of activated STATy (PIASy) and the co-chaperone protein FKBP52 which are incompatible with successful implantation. Therapeutic interventions with tacrolimus abrogated these perturbations in endometrial PGR-mediated actions, restored glycemic control, promoted implantation and significantly inhibited fetal demise and malformations. Comparative studies with metformin suggested that factors beyond glycemic control are critically involved in the pathogenesis of failed implantation and diabetes- associated fetal malformations in the obese and diabetic subjects. These findings provide insights into molecular mechanisms linked to implantation failure in diabetes, and evidently demonstrate reproductive benefits for the pre-conceptional use of macrolide immunosuppression in subjects at risk thereof.
URI for this recordhttp://hdl.handle.net/1974/22715
Request an alternative formatIf you require this document in an alternate, accessible format, please contact the Queen's Adaptive Technology Centre
The following license files are associated with this item: